Browse Month: October 2008

Treatment of potentially resectable disease


Because adenocarcinomas of the pancreatic body and tail do not cause obstruction of the intrapancreatic portion of the common bile duct, early diagnosis is rare; virtually all patients have locally advanced or metastatic disease at the time of diagnosis. CT provides an excellent assessment of the relationship of the tumor to the celiac axis and the SMA origin. Arterial encasement is present in most patients, except for the anecdotal patient who presents with upper gastrointestinal hemorrhage resulting from sinistral hypertension secondary to splenic vein occlusion by a small tumor. In the rare patient who appears to have resectable disease (no arterial encasement and no extrapancreatic disease), laparoscopy before laparotomy is a logical approach because peritoneal metastases are frequently found. The scant data available regarding surgical resection confirm the short survival and poor prognosis in this subgroup of patients. Further, the high 30-day hospital mortality rate (43%; 6 of 14 patients with adenocarcinoma) reported in a study from the Department of Veterans Affairs hospitals suggests that many of the patients taken to surgery have advanced disease and a poor performance status. Accurate preoperative imaging and a selective approach to surgical therapy will minimize treatment-related morbidity and mortality and maximize the length and quality of patient survival.



External-beam radiation therapy (EBRT) and concomitant 5-FU chemotherapy (chemoradiation) were shown to prolong survival in patients with locally advanced adenocarcinoma of the pancreas. Those data were the foundation for a prospective randomized study of adjuvant chemoradiation (500 mg/m2 /d 5-FU for 6 days and 40 Gy of radiation) following pancreaticoduodenectomy conducted by the Gastrointestinal Tumor Study Group (GITSG); that trial also demonstrated a survival advantage from multimodality therapy compared with resection alone. However, because of a prolonged recovery, 5 (24%) of the 21 patients in the adjuvant chemoradiation arm could not begin chemoradiation until more than 10 weeks after pancreaticoduodenectomy.

Further, published studies advocating postoperative adjuvant chemoradiation are prone to selection bias; the patients likely to be considered for protocol entry are those who recover rapidly from surgery and have a good performance status.

The slow patient accrual of postoperative adjuvant therapy studies and the positive correlation of survival with performance status in the GITSG trial validate this concern. A similar selection bias is likely in effect when attempts are made to retrospectively compare patients who received postoperative adjuvant chemoradiation with patients who were treated only with pancreaticoduodenectomy. However, recently reported data from Yeo and colleagues at Johns Hopkins University add further support to the use of multimodality therapy. Those investigators reviewed all patients who underwent pancreaticoduodenectomy for adenocarcinoma of the pancreatic head during a 4-year period. Fifty-six patients received adjuvant chemoradiation, and 22 underwent pancreaticoduodenectomy alone. Despite the chemoradiation group containing a larger percentage of patients with aneuploid tumors, median survival for that group was 20 months compared with 12 months for the group who received surgery alone.

A survival advantage was also demonstrated for patients treated with adjuvant combination chemotherapy alone (5-FU, doxorubicin, mitomycin C) after pancreatectomy. Median survival was 23 months in the 30 patients randomized to receive adjuvant therapy compared with 11 months in the 31 patients treated with surgery alone. Forty-six additional patients were ineligible following surgery, attesting to the difficulty in performing multiinstitution protocol-based research following a complex surgical procedure such as pancreaticoduodenectomy. The toxicity of the surgery and chemotherapy was significant; only 24 of 30 patients received chemotherapy, and only 13 of these received all 6 planned courses of chemotherapy. A previous pilot study of adjuvant 5-FU, doxorubicin, and mitomycin C, using a different schedule of administration, found similar toxicity and therefore questioned the use of adjuvant combination chemotherapy, of even moderate toxicity, after pancreatectomy.

Pretreatment diagnostic studies


If the primary tumor cannot be resected completely, surgery (pancreaticoduodenectomy) for pancreatic cancer offers no survival advantage. However, only 16% to 30% of patients who undergo operation with curative intent have their tumors successfully removed; the remaining patients are found to have unsuspected liver or peritoneal metastases or local tumor extension to the mesenteric vessels. Therefore, most patients who undergo surgical exploration for presumed cancer of the pancreatic head receive no survival benefit, yet the laparotomy results in a perioperative morbidity rate of 20% to 30%, a mean hospital stay of 14 to 20 days, and a median survival after surgery of only 6 months. Further, in patients whose tumors are resected with positive margins (Table 32.4-8) (Table Not Available) , the survival duration is less than 1 year and no different from the survival duration achieved with palliative chemotherapy and irradiation in patients who have locally advanced, unresectable disease. Therefore, in contrast to the case for selected patients with colorectal or gastric cancer, there are no data in support of palliative (positive-margin) resection for adenocarcinoma of the pancreas.


Accurate preoperative assessment of resectability will increase resectability rates and minimize positive-margin resections. A common misconception in pancreatic tumor surgery is that resectability is determined best at laparotomy. In fact, however, resectability is most accurately determined preoperatively by imaging studies, not at the time of “exploratory” laparotomy. Surgeons will declare a tumor to be unresectable at the time of laparotomy when unsuspected liver metastases, peritoneal implants, or, most commonly, locally advanced disease is found. The term locally advanced is often poorly defined, leaving the patient, the medical oncologist, and the radiation oncologist without a clear understanding of why the primary tumor was not resected. Data from MDACC have demonstrated improved rates of resectability when high-quality CT is combined with objective preoperative criteria for resectability. CT criteria for resectability include (1) the absence of extrapancreatic disease, (2) a patent superior mesenteric-portal vein (SMPV) confluence, and (3) no direct tumor extension to the celiac axis or SMA. Patients whose tumors are deemed unresectable by these radiographic criteria are not considered candidates for a potentially curative resection.

Computed Tomography

Improved CT technology over the past decade has resulted in CT being the study of choice to determine extent of disease and resectability status in patients with pancreatic cancer. Image resolution has improved considerably with the use of dynamic scanning, whereby intravenous contrast material is delivered by an automatic injector. The development of helical or spiral scanning has improved scan speed through continuous rotation of the x-ray tube around the gantry. This allows the entire pancreas to be imaged during the bolus phase of contrast enhancement. In addition, scan data can be processed to display images in three-dimensional and multiplanar formats. Helical CT performed with contrast enhancement and a thin-section technique can accurately assess the relationship of the low-density tumor to the celiac axis, SMA, and SMPV confluence. However, design of the scanning protocol and interpretation of scans must be done by experienced physicians who understand the clinical importance of accurate staging and assessment of resectability in patients with pancreatic cancer.

Controversy Over Fine-Needle Aspiration and Intraoperative Biopsy

CT-guided percutaneous fine-needle aspiration (FNA) is the diagnostic procedure of choice for establishing a cytologic diagnosis in patients with locally advanced and metastatic pancreatic cancer. The wisdom of percutaneous biopsy has recently been questioned, and several authors have suggested that the use of preoperative FNA results in peritoneal contamination by tumor cells–contamination that otherwise would not have occurred. However, only in the subgroup of patients with resectable disease are fears of FNA-induced tumor dissemination worthy of consideration; patients who have unresectable disease or who undergo a positive-margin resection have a median survival of only 6 to 12 months, and it is unlikely that microscopic contamination of the peritoneal cavity by tumor cells during biopsy would influence survival of such a short duration. In addition, the majority of patients with unresectable disease require tissue confirmation of adenocarcinoma to enable appropriate counseling and treatment planning. Given the currently available minimally invasive methods of tissue acquisition and biliary decompression, it is unrealistic to consider laparotomy with intraoperative biopsy as an alternative to CT-guided FNA in patients with advanced disease. In patients with potentially resectable disease, the concern about biopsy-induced peritoneal contamination by tumor cells has led to the recommendation that patients with clinical and radiographic findings suggestive of a malignant neoplasm of the pancreas or periampullary region undergo pancreaticoduodenectomy without tissue diagnosis. In one report, CT-guided-FNA was proposed as a cause of positive peritoneal washings in six patients. However, each of these patients appears to have had advanced, unresectable disease, which could have been the source of positive washings. Five of the six reports on the cytologic analysis of peritoneal washings have involved patients with locally advanced or unresectable adenocarcinoma of the pancreas. None of the 38 patients found to have positive washings in these five published series underwent a potentially curative pancreaticoduodenectomy; one patient underwent a palliative resection with grossly positive margins.

At the University of Texas M.D

At the University of Texas M.D. Anderson Cancer Center (MDACC), the surgeon and pathologist evaluate each specimen first by frozen-section examination of the common bile duct transection margin and the pancreatic transection margin. The retroperitoneal margin is defined as the soft-tissue margin directly adjacent to the proximal 3 to 4 cm of the superior mesenteric artery (SMA) (Fig. 32.4-1) (Figure Not Available) , and is evaluated by permanent-section examination of a 2- to 3-mm full-face (en-face) section of the margin. The retroperitoneal margin must be taken at the time of tumor resection by the pathologist and surgeon. Identification of this margin of resection is not possible once the gross examination of the specimen has been completed. A positive bile duct or pancreatic transection margin is treated with re-resection; this is not possible in the retroperitoneum, where the aorta and SMA origin limit the extent of surgical resection. Samples of multiple areas of each tumor, including the interface between tumor and adjacent uninvolved tissue, are submitted for paraffin-embedded histologic examination (5 to 10 blocks). Sections 4 mum thick are cut and stained with hematoxylin and eosin. Final pathologic evaluation of permanent sections includes a description of tumor histology and differentiation; gross and microscopic evaluation of the tissue of origin (pancreas, bile duct, ampulla of Vater (or duodenum); and assessments of maximal transverse tumor diameter, lymph node status, and the presence or absence of perineural, lymphatic, and vascular invasion (Table 32.4-6) (Table Not Available) . When segmental resection of the superior mesenteric vein (SMV) is required, the area of presumed tumor invasion of the vein wall is serially sectioned and examined in an attempt to discriminate benign fibrous attachment from direct tumor invasion. In patients who received preoperative chemoradiation, the grade of treatment effect is assessed on permanent sections using the grading schema developed by Cleary and reported by Evans and coworkers.

The method for classifying subsets of regional lymph nodes in pancreaticoduodenectomy specimens is based on the work of Cubilla and colleagues. The soft fibrofatty tissue containing regional lymph nodes is divided into six regions as outlined on the anatomic pathology dissection board (Fig. 32.4-2) (Figure Not Available) . If lymph nodes are not identified, fat or other potentially neoplastic tissue is submitted for microscopic examination. Staley and colleagues have demonstrated that the number of lymph nodes identified in the surgical specimen is increased by the use of a standardized system of specimen analysis. The dissection board illustrated in Figure 32.4-2 (Figure Not Available) provides a simple means of improving lymph node identification and documenting the location of histologically confirmed lymph node metastases. In contrast, the Japanese staging system, which involves extremely detailed analysis of margins and lymph node groups, is not a practical system for widespread application.
As the use of multimodality treatment strategies for pancreatic cancer becomes more common, it will be even more important to standardize pathologic assessment of tumor specimens.

Clinical staging

A standardized system for the clinical and pathologic staging of pancreatic cancer does not currently exist in the United States. The system modified from the American Joint Committee on Cancer and the TNM Committee of the International Union Against Cancer appears in Table 32.4-4 (Table Not Available) . However, this staging system is rarely used because it is difficult to apply, the stages do not directly correlate with treatment or prognosis, and lymph node status cannot be determined without surgical treatment. Pathologic staging can be applied only to patients who undergo pancreatectomy; in all other patients, only clinical staging, based on radiographic examinations, can be done. Treatment and prognosis are based on whether the tumor is potentially resectable, locally advanced, or metastatic, definitions that do not directly correlate with TNM status. For example, both potentially resectable and locally advanced tumors may be stage T3. Further, because lymph node metastases are often small (2 to 4 mm) and not accurately assessed by preoperative imaging, many patients who undergo complete negative-margin pancreaticoduodenectomy are found to have positive regional lymph nodes on permanent-section pathologic analysis of the resected specimen. Such patients would then be classified as having stage III disease. However, a patient with unresectable, locally advanced disease is usually classified as having stage II (T3, N0) disease because operative (pathologic) staging is not performed.

Tumors of the pancreas are unlike other solid tumors of the gastrointestinal tract in that accurate diagnosis, clinical staging, and pathologic evaluation of resected specimens require extensive interaction and cooperation between physicians of different specialties. Accurate clinical staging requires high-quality computed tomography (CT) to accurately define the relationship of the tumor to the celiac axis and superior mesenteric vessels. The development of objective radiographic criteria for preoperative tumor staging allows physicians to develop detailed treatment plans for their patients, avoid unnecessary laparotomy in patients with locally advanced or metastatic disease, and improve resectability rates.
Similar standardized criteria are needed for the pathologic analysis of pancreaticoduodenectomy specimens to allow accurate interpretation of survival statistics.

 Retrospective pathologic analysis of archival material does not allow accurate assessment of margins of resection or number of lymph nodes retrieved. However, these are the most accurate predictors of outcome. In the recent study by Yeo and colleagues, resection margin, lymph node status, and tumor size and DNA content were the tumor characteristics that most strongly predicted survival by multivariate analysis. To determine which patient subsets may benefit from the most aggressive treatment strategies, accurate pathologic staging and histologic assessment of response are mandatory.

Natural history


Rational anticancer therapy for solid malignancies is based on an accurate knowledge of the natural history and patterns of treatment failure for each tumor type. Pancreatic cancer spreads early to regional lymph nodes, and subclinical liver metastases are present in the majority of patients at the time of diagnosis, even when findings from imaging studies are normal. Patient survival depends on the extent of disease and performance status at diagnosis. Extent of disease is best categorized as resectable, locally advanced, or metastatic. Patients who undergo surgical resection for localized nonmetastatic adenocarcinoma of the pancreatic head have a long-term survival rate of approximately 20% and a median survival of 15 to 19 months (Table 32.4-2) (Table Not Available) . As will be discussed, survival is clearly maximized by combining surgery with either preoperative or postoperative 5-fluorouracil (5-FU)-based chemotherapy and radiation therapy (chemoradiation). However, disease recurrence following a potentially curative pancreaticoduodenectomy remains common. Local recurrence occurs in up to 85% of patients who undergo surgery alone; local-regional tumor control is maximized with combined-modality therapy in the form of chemoradiation and surgery. With improved local-regional disease control, liver metastases become the dominant form of tumor recurrence and occur in 50% to 70% of patients following potentially curative combined-modality treatment.
Patients with locally advanced, nonmetastatic disease have a median survival of 6 to 10 months. A survival advantage has been demonstrated for patients with locally advanced disease treated with 5-FU-based chemoradiation compared with no treatment or radiation therapy alone. Patients with metastatic disease have a short survival (3 to 6 months), the length of which depends on the extent of disease and performance status.

Knowledge of the prognosis and patterns of treatment failure associated with adenocarcinoma of the pancreas leads to the following basic treatment principles:

The treatment must not be worse than the disease. The low cure rate and modest median survival following pancreatectomy mandate that treatment-related morbidity be low and treatment-related death be rare.

2.Improvements in patient survival and quality of life will result from the development of innovative treatment strategies directed at the known sites of tumor recurrence. Data to date have clearly demonstrated that as local-regional treatment becomes more effective, the dominant site of failure has shifted to hepatic metastases.

Therefore, future improvements in survival duration will result either from effective systemic or regional therapy directed at subclinical liver metastases or from strategies for screening and early diagnosis directed at increasing the number of patients eligible for potentially curative surgery. Future improvements in the quality of patient survival will result from the application of innovative multimodality therapy to carefully selected (staged) patients and the avoidance of unnecessary patient morbidity due to the inappropriate use of surgery, radiation, or chemotherapy or any combination thereof in poorly selected (advanced disease) patients.

Pathology and molecular pathogenesis


The normal pancreatic architecture is characteristic of a secretory gland: a background of acinar cells accounts for approximately 80% of the cell number and volume of the gland; 1% to 2% are clusters of islet cells; 10% to 15% are single-layered, cuboidal ductal cells; and there is a sparse interlacing network of blood vessels, lymphatics, nerves, and collagenous stroma. This architecture is markedly altered in carcinoma, in which the predominant histologic feature is a dense collagenous stroma with atrophic acini, remarkably preserved islet cell clusters, and a slight to moderate increase in the number of ducts, both normal-appearing and cancerous. The diagnosis of ductal adenocarcinoma rests on the identification of mitoses, nuclear and cellular pleomorphism, discontinuity of ductal epithelium, and evidence of perineural, vascular, or lymphatic invasion.


The lack of obvious clinical signs and symptoms delays diagnosis in most patients. Jaundice, due to extrahepatic biliary obstruction, is present in approximately 50% of patients at diagnosis and is associated with a less advanced stage of disease than are other signs or symptoms. Small tumors of the pancreatic head may obstruct the intrapancreatic portion of the bile duct and cause the patient to seek medical attention when the tumor is still localized and potentially resectable. In the absence of extrahepatic biliary obstruction, few patients present with potentially resectable disease.

The pain typical of locally advanced pancreatic cancer is a dull, fairly constant pain of visceral origin localized to the region of the middle and upper back. The pain is due to tumor invasion of the celiac and mesenteric plexus. Vague, intermittent epigastric pain occurs in some patients; its etiology is less clear. Fatigue, weight loss, and anorexia are common even in the absence of mechanical gastric outlet obstruction. Pancreatic exocrine insufficiency due to obstruction of the pancreatic duct may result in malabsorption and steatorrhea. Although malabsorption and mild changes in stool frequency are common, diarrhea occurs infrequently.

Glucose intolerance is present in most patients with pancreatic cancer. Although the exact mechanism of hyperglycemia remains unclear, both altered beta-cell function and impaired tissue insulin sensitivity are present. The importance of islet cell function to the development of exocrine cancer is suggested by the work of Bell and Stayer, who demonstrated that pretreatment of hamsters with streptozocin and the resulting destruction of islet cells prevented the induction of pancreatic cancer in these animals by the carcinogen N-nitrosobis-(2-oxopropyl)amine (BOP). This work was substantiated by studies in Chinese hamsters demonstrating that only genetically diabetic animals did not develop cancers in response to N-nitroso-(2-oxopropyl)amine.

In the absence of jaundice, patient complaints are nonspecific, as are clinical signs on physical examination. However, important staging information with direct implications for therapy can be obtained from the physical examination. This information includes performance status, cardiopulmonary function, and the presence or absence of left supraclavicular adenopathy and ascites.

Familial pancreatic cancer

The recent emergence of the importance of inherited genetic abnormalities in gastrointestinal tract neoplasia has led to closer investigation of the potential role for heritable factors in pancreatic cancer. Several rare hereditary disorders predispose persons to both endocrine and exocrine pancreatic cancer. These include the multiple endocrine neoplasia type I syndrome, hereditary pancreatitis, Lynch syndrome II, von Hippel-Lindau syndrome, ataxia-telangiectasia, and possibly the familial atypical multiple mole melanoma syndrome. In addition, case reports and formal epidemiologic studies have suggested the possibility of familial aggregations of pancreatic cancer outside the context of these rare familial syndromes. One case-control study estimated that 3% of pancreatic cancers had a hereditary origin. Evaluation of approximately 30 extended families with presumed familial pancreatic cancer has suggested that transmission is consistent with an autosomal dominant pattern. The age at onset, tumor histopathology, male preponderance, and overall survival of persons affected by pancreatic cancer in these families are reported to be similar to those of persons with pancreatic cancer in the general population. Continued study of these patients and their families may provide insight into the critical molecular genetic abnormalities leading to familial pancreatic cancer. Familial genetic abnormalities may then provide insight into the process of pancreatic carcinogenesis for patients with sporadic pancreatic cancer and provide opportunities for early detection and chemoprevention.


Exposure to certain chemicals, usually in a manufacturing setting, has been associated with an increased risk of pancreatic cancer. Previous studies implicated 2-naphthylamine, benzidine, and derivatives of gasoline. More recently, a cohort mortality study of more than 5000 chemical manufacturing workers suggested that heavy and prolonged exposure to DDT and related compounds can cause pancreatic cancer in humans. Finally, specific occupations (e.g., stone miners, cement workers, gardeners, and textile workers) have been associated with an increased risk of pancreatic cancer; however, the specific causative factors or carcinogens accounting for this increase are unclear. Currently, most newly diagnosed patients with pancreatic cancer do not have evidence of a specific chemical exposure or relevant occupational history. Other factors, such as smoking and diet, will probably play a much greater overall role in determining individual risk of pancreatic cancer.